Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder

Marisa W. Friederich; Sharita Timal; Christopher A. Powell; Cristina Dallabona; Alina Kurolap; Sara Palacios-Zambrano; Drago Bratkovic; Terry G.J. Derks; David Bick; Katelijne Bouman; Kathryn C. Chatfield; Nadine Damouny-Naoum; Megan K. Dishop; Tzipora C. Falik-Zaccai; Fuad Fares; Ayalla Fedida; Ileana Ferrero; Renata C. Gallagher; Rafael Garesse; Micol Gilberti; Cristina González; Katherine Gowan; Clair Habib; Rebecca K. Halligan; Limor Kalfon; Kaz Knight; Dirk Lefeber; Laura Mamblona; Hanna Mandel; Adi Mory; John Ottoson; Tamar Paperna; Ger J.M. Pruijn; Pedro F. Rebelo-Guiomar; Ann Saada; Bruno Sainz; Hayley Salvemini; Mirthe H. Schoots; Jan A. Smeitink; Maciej J. Szukszto; Hendrik J. ter Horst; Frans van den Brandt; Francjan J. van Spronsen; Joris A. Veltman; Eric Wartchow; Liesbeth T. Wintjes; Yaniv Zohar; Miguel A. Fernández-Moreno; Hagit N. Baris; Claudia Donnini; Michal Minczuk; Richard J. Rodenburg; Johan L.K. Van Hove

doi:10.1038/s41467-018-06250-w

Pathogenic variants in glutamyl-tRNA^Gln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder

Marisa W. Friederich, Sharita Timal, Christopher A. Powell, Cristina Dallabona, Alina Kurolap, Sara Palacios-Zambrano, Drago Bratkovic, Terry G.J. Derks, David Bick, Katelijne Bouman, Kathryn C. Chatfield, Nadine Damouny-Naoum, Megan K. Dishop, Tzipora C. Falik-Zaccai, Fuad Fares, Ayalla Fedida, Ileana Ferrero, Renata C. Gallagher, Rafael Garesse, Micol GilbertiCristina González, Katherine Gowan, Clair Habib, Rebecca K. Halligan, Limor Kalfon, Kaz Knight, Dirk Lefeber, Laura Mamblona, Hanna Mandel, Adi Mory, John Ottoson, Tamar Paperna, Ger J.M. Pruijn, Pedro F. Rebelo-Guiomar, Ann Saada, Bruno Sainz, Hayley Salvemini, Mirthe H. Schoots, Jan A. Smeitink, Maciej J. Szukszto, Hendrik J. ter Horst, Frans van den Brandt, Francjan J. van Spronsen, Joris A. Veltman, Eric Wartchow, Liesbeth T. Wintjes, Yaniv Zohar, Miguel A. Fernández-Moreno, Hagit N. Baris, Claudia Donnini, Michal Minczuk, Richard J. Rodenburg, Johan L.K. Van Hove

Research output: Contribution to journal › Article › peer-review

Abstract

Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNA^Gln). mt-tRNA^Gln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNA^Gln and mitochondrial protein translation are deficient in patients’ fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.

Original language	English
Article number	4065
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06250-w
State	Published - 1 Dec 2018

Bibliographical note

Funding Information:
We would like to thank the families for their participation in this study. We thank the mitochondrial diagnostics group (muscle lab, cell culture lab, and DNA lab) of the Radboud Center for Mitochondrial Medicine (RCMM) at the Translational Metabolic Laboratory, Radboud UMC, as well as Carla Onnekink, Jeff Willemsen, Daisy Dalloyaux, and Sander van de Groenendaal for excellent technical assistance. Mareike Muhlmeister and Ulrich Brandt are thanked for performing mass spectrometry experiments. We would like to acknowledge the Genome Technology Center at the Radboud UMC and BGI Copenhagen for providing the exome sequencing service for patients P1A and P1B. We like to thank the staff of the Colorado Fetal Care Center, the Children’s Hospital Colorado fetal cardiology and neonatology programs and C. Freehauf, RN, CGC for the expert clinical care of family 3. C.A.P., M.J.S., P.R.-G. and M.M. were supported by the core funding from the Medical Research Council, UK (MC_U105697135 and MC_UU_00015/4). J.V.H. and M.W.F. were supported by Miracles for Mito, the Children’s Hospital Colorado Foundation and University of Colorado Foundation. This work was supported by Telethon Foundation, Italy grant GGP15041 to C.D. This work was also supported by Instituto de Salud Carlos III, http:// www.isciii.es/, PI13/00556 to R.G.; FEDER funds from the E.U. to R.G. and Instituto de Salud Carlos III, http://www.isciii.es/, PI16/00789 to R.G. and M.A.F-M. P.R.-G. was supported by Fundação para a Ciência e a Tecnologia (PD/BD/105750/2014).

Publisher Copyright:
© 2018, © 2018, The Author(s).

ASJC Scopus subject areas

Chemistry (all)
Biochemistry, Genetics and Molecular Biology (all)
Physics and Astronomy (all)

Access to Document

10.1038/s41467-018-06250-w

Cite this

Friederich, M. W., Timal, S., Powell, C. A., Dallabona, C., Kurolap, A., Palacios-Zambrano, S., Bratkovic, D., Derks, T. G. J., Bick, D., Bouman, K., Chatfield, K. C., Damouny-Naoum, N., Dishop, M. K., Falik-Zaccai, T. C., Fares, F., Fedida, A., Ferrero, I., Gallagher, R. C., Garesse, R., ... Van Hove, J. L. K. (2018). Pathogenic variants in glutamyl-tRNA^Gln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder. Nature Communications, 9(1), [4065]. https://doi.org/10.1038/s41467-018-06250-w

@article{880871cee08741d78169ec485e3af5ed,

title = "Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder",

abstract = "Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients{\textquoteright} fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.",

author = "Friederich, {Marisa W.} and Sharita Timal and Powell, {Christopher A.} and Cristina Dallabona and Alina Kurolap and Sara Palacios-Zambrano and Drago Bratkovic and Derks, {Terry G.J.} and David Bick and Katelijne Bouman and Chatfield, {Kathryn C.} and Nadine Damouny-Naoum and Dishop, {Megan K.} and Falik-Zaccai, {Tzipora C.} and Fuad Fares and Ayalla Fedida and Ileana Ferrero and Gallagher, {Renata C.} and Rafael Garesse and Micol Gilberti and Cristina Gonz{\'a}lez and Katherine Gowan and Clair Habib and Halligan, {Rebecca K.} and Limor Kalfon and Kaz Knight and Dirk Lefeber and Laura Mamblona and Hanna Mandel and Adi Mory and John Ottoson and Tamar Paperna and Pruijn, {Ger J.M.} and Rebelo-Guiomar, {Pedro F.} and Ann Saada and Bruno Sainz and Hayley Salvemini and Schoots, {Mirthe H.} and Smeitink, {Jan A.} and Szukszto, {Maciej J.} and {ter Horst}, {Hendrik J.} and {van den Brandt}, Frans and {van Spronsen}, {Francjan J.} and Veltman, {Joris A.} and Eric Wartchow and Wintjes, {Liesbeth T.} and Yaniv Zohar and Fern{\'a}ndez-Moreno, {Miguel A.} and Baris, {Hagit N.} and Claudia Donnini and Michal Minczuk and Rodenburg, {Richard J.} and {Van Hove}, {Johan L.K.}",

note = "Funding Information: We would like to thank the families for their participation in this study. We thank the mitochondrial diagnostics group (muscle lab, cell culture lab, and DNA lab) of the Radboud Center for Mitochondrial Medicine (RCMM) at the Translational Metabolic Laboratory, Radboud UMC, as well as Carla Onnekink, Jeff Willemsen, Daisy Dalloyaux, and Sander van de Groenendaal for excellent technical assistance. Mareike Muhlmeister and Ulrich Brandt are thanked for performing mass spectrometry experiments. We would like to acknowledge the Genome Technology Center at the Radboud UMC and BGI Copenhagen for providing the exome sequencing service for patients P1A and P1B. We like to thank the staff of the Colorado Fetal Care Center, the Children{\textquoteright}s Hospital Colorado fetal cardiology and neonatology programs and C. Freehauf, RN, CGC for the expert clinical care of family 3. C.A.P., M.J.S., P.R.-G. and M.M. were supported by the core funding from the Medical Research Council, UK (MC_U105697135 and MC_UU_00015/4). J.V.H. and M.W.F. were supported by Miracles for Mito, the Children{\textquoteright}s Hospital Colorado Foundation and University of Colorado Foundation. This work was supported by Telethon Foundation, Italy grant GGP15041 to C.D. This work was also supported by Instituto de Salud Carlos III, http:// www.isciii.es/, PI13/00556 to R.G.; FEDER funds from the E.U. to R.G. and Instituto de Salud Carlos III, http://www.isciii.es/, PI16/00789 to R.G. and M.A.F-M. P.R.-G. was supported by Funda{\c c}{\~a}o para a Ci{\^e}ncia e a Tecnologia (PD/BD/105750/2014). Publisher Copyright: {\textcopyright} 2018, {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-06250-w",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

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Friederich, MW, Timal, S, Powell, CA, Dallabona, C, Kurolap, A, Palacios-Zambrano, S, Bratkovic, D, Derks, TGJ, Bick, D, Bouman, K, Chatfield, KC, Damouny-Naoum, N, Dishop, MK, Falik-Zaccai, TC, Fares, F, Fedida, A, Ferrero, I, Gallagher, RC, Garesse, R, Gilberti, M, González, C, Gowan, K, Habib, C, Halligan, RK, Kalfon, L, Knight, K, Lefeber, D, Mamblona, L, Mandel, H, Mory, A, Ottoson, J, Paperna, T, Pruijn, GJM, Rebelo-Guiomar, PF, Saada, A, Sainz, B, Salvemini, H, Schoots, MH, Smeitink, JA, Szukszto, MJ, ter Horst, HJ, van den Brandt, F, van Spronsen, FJ, Veltman, JA, Wartchow, E, Wintjes, LT, Zohar, Y, Fernández-Moreno, MA, Baris, HN, Donnini, C, Minczuk, M, Rodenburg, RJ & Van Hove, JLK 2018, 'Pathogenic variants in glutamyl-tRNA^Gln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder', Nature Communications, vol. 9, no. 1, 4065. https://doi.org/10.1038/s41467-018-06250-w

TY - JOUR

T1 - Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder

AU - Friederich, Marisa W.

AU - Timal, Sharita

AU - Powell, Christopher A.

AU - Dallabona, Cristina

AU - Kurolap, Alina

AU - Palacios-Zambrano, Sara

AU - Bratkovic, Drago

AU - Derks, Terry G.J.

AU - Bick, David

AU - Bouman, Katelijne

AU - Chatfield, Kathryn C.

AU - Damouny-Naoum, Nadine

AU - Dishop, Megan K.

AU - Falik-Zaccai, Tzipora C.

AU - Fares, Fuad

AU - Fedida, Ayalla

AU - Ferrero, Ileana

AU - Gallagher, Renata C.

AU - Garesse, Rafael

AU - Gilberti, Micol

AU - González, Cristina

AU - Gowan, Katherine

AU - Habib, Clair

AU - Halligan, Rebecca K.

AU - Kalfon, Limor

AU - Knight, Kaz

AU - Lefeber, Dirk

AU - Mamblona, Laura

AU - Mandel, Hanna

AU - Mory, Adi

AU - Ottoson, John

AU - Paperna, Tamar

AU - Pruijn, Ger J.M.

AU - Rebelo-Guiomar, Pedro F.

AU - Saada, Ann

AU - Sainz, Bruno

AU - Salvemini, Hayley

AU - Schoots, Mirthe H.

AU - Smeitink, Jan A.

AU - Szukszto, Maciej J.

AU - ter Horst, Hendrik J.

AU - van den Brandt, Frans

AU - van Spronsen, Francjan J.

AU - Veltman, Joris A.

AU - Wartchow, Eric

AU - Wintjes, Liesbeth T.

AU - Zohar, Yaniv

AU - Fernández-Moreno, Miguel A.

AU - Baris, Hagit N.

AU - Donnini, Claudia

AU - Minczuk, Michal

AU - Rodenburg, Richard J.

AU - Van Hove, Johan L.K.

N1 - Funding Information: We would like to thank the families for their participation in this study. We thank the mitochondrial diagnostics group (muscle lab, cell culture lab, and DNA lab) of the Radboud Center for Mitochondrial Medicine (RCMM) at the Translational Metabolic Laboratory, Radboud UMC, as well as Carla Onnekink, Jeff Willemsen, Daisy Dalloyaux, and Sander van de Groenendaal for excellent technical assistance. Mareike Muhlmeister and Ulrich Brandt are thanked for performing mass spectrometry experiments. We would like to acknowledge the Genome Technology Center at the Radboud UMC and BGI Copenhagen for providing the exome sequencing service for patients P1A and P1B. We like to thank the staff of the Colorado Fetal Care Center, the Children’s Hospital Colorado fetal cardiology and neonatology programs and C. Freehauf, RN, CGC for the expert clinical care of family 3. C.A.P., M.J.S., P.R.-G. and M.M. were supported by the core funding from the Medical Research Council, UK (MC_U105697135 and MC_UU_00015/4). J.V.H. and M.W.F. were supported by Miracles for Mito, the Children’s Hospital Colorado Foundation and University of Colorado Foundation. This work was supported by Telethon Foundation, Italy grant GGP15041 to C.D. This work was also supported by Instituto de Salud Carlos III, http:// www.isciii.es/, PI13/00556 to R.G.; FEDER funds from the E.U. to R.G. and Instituto de Salud Carlos III, http://www.isciii.es/, PI16/00789 to R.G. and M.A.F-M. P.R.-G. was supported by Fundação para a Ciência e a Tecnologia (PD/BD/105750/2014). Publisher Copyright: © 2018, © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients’ fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.

AB - Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients’ fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.

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U2 - 10.1038/s41467-018-06250-w

DO - 10.1038/s41467-018-06250-w

M3 - Article

C2 - 30283131

AN - SCOPUS:85054370449

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

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ER -